The most effective intervention to prevent infectious diseases is vaccination. DNA vaccines have unique features that make them advantageous candidates to replace or add to whole virus or recombinant subunit vaccines. In mimicking natural protein expression including secondary modifications, plasmid DNA vaccines can evoke both humoral responses including neutralizing antibodies to conformational viral epitopes and cell-mediated responses. They are easy to manufacture and clinical trials thus far indicate that they are well tolerated. However, their efficacy in clinical trials has in general been disappointing. Increasing their efficacy should be a high priority. Low efficacy in humans as opposed to rodents seems due to the relative small amount of antigen produced and the relatively low number of antigen presenting cells transduced with DNA plasmids. We intend to ameliorate these drawbacks of DNA vaccines and propose to make DNA vaccines more efficient by adding two properties used by infectious DNA viruses to usurp the cells machinery, essentially providing the DNA vector with properties that allow infecting viruses to transcribe efficiently. The first change to the plasmid will mimic how DNA viruses (including recombinant adenoviral vaccine carriers) use specific nuclear organelles for their efficient immediate early transcription thus increasing the potential for producing more antigen per transfected cell. The second change will mimic the viral transmission of a specific antigen from the infected producer cell, to many other uninfected recipient cells thus amplifying the number of cells that can present antigen. We will add a third property by targeting and depositing the antigen to the nuclear site of immunoproteosome activity capitalizing on the recently recognized capacity to produce antigenic peptides in the nucleus. The combined effects of these three changes to the vector are expected to substantially amplify the immune response by DNA vaccination relative to that achieved by current vectors.